Skin is formed by three layers: stratum corneum, dermis and epidermis. The stratum corneum is the outermost layer and is formed by corneocytes and lipids which protect the skin from the external environment. The epidermis is composed of keratinocytes, melanocytes and Langerhans cells. The main cell population in the epidermis is keratinocytes, which form a keratinized layer that continually renews itself. Their function is to protect against external agents, whether these be physical, chemical or pathogens. The dermis is located deeper in the skin and is joined to the epidermis by means of the basal membrane. It is formed by fibroblasts, adipocytes and macrophages; it is irrigated by blood vessels and presents numerous nerve endings responsible for transmitting sensations of touch and temperature. Hair follicles as well as sweat, sebaceous and apocrine glands are located in the dermis, and their function is to maintain the integrity and elasticity of the skin.
During aging, a progressive decrease in the functions of the skin is observed giving rise, among other things, to the appearance of the heterogeneity of the skin. Thus the skin suffers changes through aging and this gradually affects its appearance showing redness, changes to the pigmentation, loss of firmness and/or the appearance of wrinkles. The continual exposure to ultraviolet radiation (UV) intensifies these changes, favoring their appearance before maturity is reached. In some individuals even disorders and/or diseases related to excessive redness or marks on the skin develop. There is, therefore, a need to develop new compounds capable of improving the appearance of the skin, standardizing its color, reducing wrinkles and improving firmness.
Redness
One of the cutaneous disorders with redness blamed as a clinical symptom that presents a higher rate of occurrence in the Caucasian race is rosacea. Rosacea is a chronic disorder or disease of the skin that is quite common, it usually appears between the ages of 3 and 50, more in women than men and particularly in Caucasian people with very pale skin. Rosacea affects the central areas of the face and is characterized by recurring episodes of itchiness, reddening, erythemas, papules, pustules, vasodilatation, telangiectasias, pain and inflammation. The symptoms of rosacea are exacerbated by exposure to sun, heat, high humidity, sweat, physical exercise, emotional stress, alcohol intake and spicy food. Furthermore, people with rosacea usually suffer from very dry skin, even presenting desquamation of the skin.
The cause of rosacea is not well established. Until recently, it was thought that the cause was some type of infectious agent, therefore antibiotics were prescribed for its treatment; however, treatments with antibiotics only provide a partial improvement. To treat rosacea and prevent abnormalities in the skin's pigmentation due to associated inflammation, antibiotics have been described such as tetracyclines, dapsone and metronidazoles. [Woolery-Lloyd H. et al. “Acne and Rosacea in Skin of Color”, Cosmetic Dermatology, (2011), 24:4, 159-162].
Recently, it has been proposed that bradykinin, a local hormone, could have a vasodilatory effect, thus increasing vascular permeability and inflammation. The group of bradykinins is produced due to kininogen hydrolysis, a protein with a low molecular weight, by an enzyme called kallikrein.
Kallikreins (KLK) are a group of serine proteases that are found in different biological tissues and fluids. Kallikreins are divided into two principal categories: plasma kallikreins and tissue kallikreins [Paliouras et al., “The kallikrein world: an update on the human tissue Kallikreins”, Biol. Chem., (2006), 387, 643-652]. Both categories differ significantly in their molecular weight, substrate specificity, immunological characteristics and genetic structure.
Tissue kallikreins are extracellular serine proteases secreted by granular keratinocytes [Eissa et al., “Human tissue kallikreins as promiscuous modulators of homeostatic skin barrier functions”. Biol. Chem., (2008), 389, 669-680].
The principal kallikreins in the stratum corneum are the KLK5, the KLK7 and the KLK14, although multiple KLKs have been detected by immunohistochemistry in the granular stratum and in the stratum corneum, both in their active and inactive form. It has been found that they are responsible for the activation of antimicrobial peptides after an infection, as well as degrading molecules responsible for adhesion between corneocytes. Kallikrein mRNA has also been detected in the epithelium follicles, which suggests the participation of KLKs in the development of hair. Furthermore, they also participate in the activity of the sebaceous glands and the formation of sebum.
KLKs are activated by means of a series of reactions in which a KLK activates a pro-KLK, thus a KLK acts as an initiator, propagator and/or executor, depending on its concentration, specificity and activity level, as with a free-radical reaction. In in vitro studies, it has been demonstrated that pro-KLK5 is activated by KLK14 and that KLK5 activates pro-KLK7 and pro-KLK14.
It has been found that in skin affected by rosacea there are levels of KLK5 higher than in healthy skin [Yamasaki et al., “Kallikrein-mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin”, the FASEB J., (2006), 20, 2068-2080]. It has also been observed that in skin affected by rosacea there is a high level of cathelicidin, a antimicrobial peptide that is processed by the enzymes of the stratum corneum such as kallikreins giving rise to its active form LL-37 involved in the inflammation and in angiogenesis [Morizane et al., “TLR2 Expression Is Increased in Rosacea and Stimulates Enhanced Serine Protease Production by Keratinocytes” J Invest Dermatol., (2010), 130(5), 1297-1306] inducing cytokine release such as interleukins (IL-6, IL-8, etc.), which are known inflammatory agents [Pistolic J et al, Host defense peptide LL-37 induces IL-6 expression in human bronchial epithelial cells by activation of the NF-kappaB signaling pathway, J Innate Immun. 2009; 1(3):254-67].
Another of the more common vascular disorders of the skin is the appearance of telangiectasias, which are generally presented as superficial cutaneous capillaries near the surface of the skin with part of the center being bright red and with radial branches. This skin condition is also known as spider veins. Telangiectasia can be stimulated by the exposure to UV radiation, stress, environmental factors, lesions and/or the aging of the skin.
Appearance of Wrinkles and Loss of Firmness
Collagen is the most abundant protein in the skin, comprising between 70-80% of the dry weight of the skin, and gives it the mechanical and structural integrity necessary to maintain its functions. There are numerous types of collagen, collagen I being the most common. It is structured in the form of fibrils that are also associated by forming collagen fibers in a process called fibrillogenesis. Other types of collagen are III, IV, VII and XII. The second most important protein in the dermis is elastin. Elastin is organized in the form of insoluble elastic fibers with a central hydrophobic nucleus surrounded by fibrillar structures. It is more of a minority protein than collagen, but is crucial in the maintenance of the elasticity and resistance of the skin.
This extra cellular connective tissue of the dermis can be damaged as a result of an inflammatory response. Aggressive climates or exposure to UV light stimulate the production of reactive species which boost the inflammatory processes of the skin and activate the proteolytic systems of the extra cellular matrix. Phagocytes released into the skin through the blood vessels can also release proteases that cause inflammation and activate matrix metalloproteinases (MMP). These MMPs degrade the collagen and elastin molecules which may have been damaged after the inflammatory process. MMP-1 degrades collagen I and III, whilst MMP-12 is the most active against elastin. The result of excessive collagen and elastin degradation is flaccid and wrinkled skin.
During aging cytokines are released (the inflammaging theory), which as well as causing inflammation, are metalloprotease (MMP) activators such as collagenase, responsible for the degradation of the principle proteins that form the extra cellular matrix of the dermis and are responsible for physically supporting the whole structure of the skin such as collagen and elastin. Cytokines are also released through exposure to ultraviolet light, one of the major causes of inflammation and photoaging of the skin.
The release of cytokines that takes place in different conditions, disorders or diseases of the skin that have an inflammatory component also affects the quality of the skin. For example, those affected by rosacea present high levels of LL-37, which in turn inhibits the expression of collagen I and Ill [Park H. J et al., “Collagen synthesis is suppressed in dermal fibroblasts by the human antimicrobial peptide LL-37”, J Invest Dermatol, 2009, 129, 843-850], which, together with a greater activity of MMPs later in life makes skin with rosacea much weaker and flaccid.
Pigmentation of the Skin
The color of the skin is chiefly determined by the quantity, distribution and type of melanin, a natural pigmented biopolymer that is synthesized in melanosomes, organules present in the melanocytes of the epidermis, in a process called melanogenesis catalyzed by tyrosinase. Tyrosinase catalyzes the two first decisive steps of melanogenesis: hydroxylation of tyrosine to form 3,4-hydroxyphenylalanine (DOPA) and the subsequent oxidation of DOPA to form DOPA-quinone. Subsequently, melanin synthesized in the melanocytes is transferred through dendrites to the keratinocytes, from where it will be distributed through the whole epidermis and the stratum corneum. This is the process that determines the coloring of the skin.
Modification of the natural pigmentation of the skin is desirable for different reasons for many people in America, Asia or Europe. Among the reasons for modifying the natural color of the skin is the search for clearer skin by beauty models and the removal or reduction of marks on the skin such as freckles or lentigines.
People affected by skin disorders or diseases with an inflammatory component are exposed to developing post-inflammatory hyperpigmentation. The coloring of the skin has been a motive for concern for human beings for many years. In particular, the ability to remove hyperpigmentation, whether it is due to age (marks, freckles or general aging of the skin), or whether it is due to disorders or diseases (melasma, chloasma, post-inflammatory hyperpigmentation) is of interest for individuals who want a uniform skin tone. Furthermore, when exposure to UV radiation is prolonged or excessive, cancerous hyperpigmented lesions or melanomas can develop [Dooley T. P., “Recent advances in cutaneous melanoma oncogenesis research”, (1994), Onco. Res., 6, 1-9] as well as benign hyperpigmented marks due to photoaging and excessive functioning of melanocytes, which synthesize more melanin than is required in an attempt to regenerate damaged skin after the inflammatory process. The result of an increase in synthesis and release of mediatory substances of inflammation such as cytokines, TNF-α, interleukin-6 and interleukin-8 is hyperpigmented skin.
The cosmetic industry has undertaken considerable efforts to develop new compounds useful in the treatment and/or care of conditions, disorders and/or diseases that improve or are prevented by the inhibition of cytokine release, the inhibition of matrix metalloproteinase activity and/or the inhibition of melanogenesis. However, although the majority of the existing compounds in the prior art are useful for the treatment and/or care of conditions, disorders and/or diseases that improve or are prevented by one or several of the aforementioned activities, it is difficult to find in the prior art compounds that present all of the aforementioned activities at the same time.